Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity±s.d. for colorectal cancer microsomes was 67.8±36.6 pmol min−1 mg−1. The Km of the tumoral enzyme (42±8 μM) is similar to that in healthy colorectal epithelium (36±8 μM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1±1.2 pmol min−1 mg−1. The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a KI value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs

Estimation of physician supply by specialty and the distribution impact of increasing female physicians in Japan

<p>Abstract</p> <p>Background</p> <p>Japan has experienced two large changes which affect the supply and distribution of physicians. They are increases in medical school enrollment capacity and in the proportion of female physicians. The purpose of this study is to estimate the future supply of physicians by specialty and to predict the associated impact of increased female physicians, as well as to discuss the possible policy implications.</p> <p>Methods</p> <p>Based on data from the 2004 and 2006 National Survey of Physicians, Dentists and Pharmacists, we estimated the future supply of physicians by specialty, using multistate life tables. Based on possible scenarios of the future increase in female physicians, we also estimated the supply of physicians by specialty.</p> <p>Results</p> <p>Even if Japan's current medical school enrollment capacity is maintained in subsequent years, the number of physicians per 1000 population is expected to increase from 2.2 in 2006 to 3.2 in 2036, which is a 46% increase from the current level. The numbers of obstetrician/gynecologists (OB/GYNs) and surgeons are expected to temporarily decline from their current level, whereas the number of OB/GYNs per 1000 births will still increase because of the declining number of births. The number of surgeons per 1000 population, even with the decreasing population, will decline temporarily over the next few years. If the percentage of female physicians continues to increase, the overall number of physicians will not be significantly affected, but in specialties with current very low female physician participation rates, such as surgery, the total number of physicians is expected to decline significantly.</p> <p>Conclusion</p> <p>At the current medical school enrollment capacity, the number of physicians per population is expected to continue to increase because of the skewed age distribution of physicians and the declining population in Japan. However, with changes in young physicians' choices of medical specialties and as the percentage of female physicians increases, patterns of physician supply will vary between specialties. Specialties less often chosen by young physicians and where males have dominated will face a decline in physician supply. These results highlight the necessity for developing a work environment that attracts female physicians to these types of specialties. This will also lead to improved gender equality in the workforce and more effective use of human resources.</p

Genetic variability in CYP3A4 and CYP3A5 in primary liver, gastric and colorectal cancer patients

<p>Abstract</p> <p>Background</p> <p>Drug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites. The role of gene polymorphisms of several cytochrome P450 enzymes in digestive cancer risk has been extensively investigated. However, the drug-metabolizing enzymes with the broader substrate specificity, CYP3A4 and CYP3A5, have not been analyzed so far. This study aims to examine associations between common CYP3A4 and CYP3A5 polymorphisms and digestive cancer risk.</p> <p>Methods</p> <p>CYP3A4 and CYP3A5 genotypes were determined in 574 individuals including 178 patients with primary liver cancer, 82 patients with gastric cancer, 151 patients with colorectal cancer, and 163 healthy individuals.</p> <p>Results</p> <p>The variant allele frequencies for patients with liver cancer, gastric cancer, colorectal cancer and healthy controls, respectively, were: <it>CYP3A4*1B</it>, 4.8 % (95% C.I. 2.6–7.0), 3.7 % (0.8–6.6) 4.3% (2.0–6.6) and 4.3% (2.1–6.5); <it>CYP3A5*3</it>, 91.8 % (93.0–97.4), 95.7% (92.6–98.8), 91.7% (88.6–94.8) and 90.8% (87.7–93.9). The association between <it>CYP3A4*1B </it>and <it>CYP3A5*3 </it>variant alleles did not significantly differ among patients and controls. No differences in genotypes, allele frequencies, or association between variant alleles were observed with regard to gender, age at diagnosis, tumour site or stage.</p> <p>Conclusion</p> <p>Common polymorphisms on <it>CYP3A4 </it>and <it>CYP3A5 </it>genes do not modify the risk of developing digestive cancers in Western Europe.</p

Comparative studies to determine the selective inhibitors for P-glycoprotein and cytochrome P 4503A4

It has been suggested that cytochrome P450 3A4 (CYP3A4) and MDR1 P-glycoprotein (P-gp) act synergistically to limit the bioavailability of orally administered agents. In order to determine the relative role of these proteins, it is essential to identify a selective inhibitor for either P-gp or CYP3A4. In the present investigation, comparative studies were performed to examine the effect of inhibitors on the function of these proteins. The IC50 of P-gp function, determined by examining the inhibition of the transcellular transport of vinblastine across Caco-2 monolayers, was in the order PSC833 ≪ ketoconazole, verapamil ≪ N-(2(R)-hydroxy-1(S)-indanyl)-5-(2(S)-(1,1-dimethylethylaminocarbonyl)-4-(furo(2,3-b)pyridin-5-yl) methyl)piperazin-1-yl)-4(S)-hydroxy-2(R)-phenylmethylpentanamide (L-754,394). In contrast, the IC50 of CYP3A4 function, determined by examining the inhibition of the metabolism of midazolam by intestinal and liver microsomes, was in the order L-754,384 ≪ketoconazole≪ PSC 833 and verapamil. The ratio of IC50 for P-gp to that for CYP3A4 was more than 200 for L-754,394,60 ∼ 150 for ketoconazole, 1.5 for verapamil, and 0.05 for PSC 833. Collectively, it was demonstrated that PSC 833 and L-754,394 can be used as selective inhibitors of P-gp and CYP3A4, respectively